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Non-Alcoholic Fatty Liver Disease PDF
Non-Alcoholic Fatty Liver Disease PDF
Introduction
The Clinical Practice Guidelines propose recommendations for (Table 1) [2]. In particular, screening for NAFLD in the popula-
the diagnosis, treatment and follow-up of non-alcoholic fatty tion at risk should be in the context of the available resources,
liver disease (NAFLD) patients and are the product of a joint effort considering the burden for the national health care systems
by the European Association for the Study of the Liver (EASL), and the currently limited effective treatments. The document
European Association for the Study of Diabetes (EASD) and Euro- is intended both for practical use and for advancing the research
pean Association for the Study of Obesity (EASO). They update a and knowledge of NAFLD in adults, with specific reference to
position statement based on the 2009 EASL Special Conference paediatric NAFLD whenever necessary. The final purpose is to
[1]. improve patient care and awareness of the importance of
The data have been retrieved by an extensive PubMed search NAFLD, and to assist stakeholders in the decision-making pro-
up to April 2015. The final statements are graded according to cess by providing evidence-based data, which also takes into
the level of evidence and strength of recommendation, which consideration the burden of clinical management for the health-
are adjustable to local regulations and/or team capacities care system.
Definition
Recommendations Steatosis
In patients with T2DM, the presence of NAFLD should Steatosis present Steatosis absent
be looked for irrespective of liver enzyme levels, since
T2DM patients are at high risk of disease progression
(A2)
Normal Abnormal3 Normal
liver enzymes liver enzymes liver enzymes
According to a priori probability or clinical evaluation. sion to NASH and fibrosis is rare for steatosis alone [49,50].
C, control arm; CBT, cognitive-behaviour therapy; E, Experimental arm; EPA, Eicosapentanoic acid; EZE, Ezetimibe; HbA1c, glycosylated haemoglobin; LIRA, liraglutide;
MET, metformin; MR, magnetic resonance; MRI, magnetic resonance imaging; NAS, NAFLD activity score; OCA, obeticholic acid; ORL, orlistat; PIO, pioglitazone; PL, placebo;
PTX, pentoxifylline; PUFA, polyunsaturated fatty acids; RSG, rosiglitazone.
loss P7% was associated with histological improvement. In an Pragmatic approaches combining dietary restriction and a pro-
uncontrolled, 12-month study with 261 paired biopsies, a modest gressive increase in aerobic exercise/resistance training [121] are
lifestyle-induced weight loss was associated with NASH regres- preferable and should be individually tailored. No data are avail-
sion (25% of total cases) without worsening of fibrosis [120]. able on their long-term effects on the natural history of NAFLD.
Antioxidants, cytoprotective and lipid lowering agents Statins may be confidently used to reduce LDL-
In the PIVENS trial, vitamin E (800 IU/day) improved steatosis, cholesterol and prevent cardiovascular risk, with no
inflammation and ballooning and induced resolution of NASH benefits or harm on liver disease. Similarly n-3
in 36% of patients (21% in the placebo arm) [95]. Reduced ALT polyunsaturated fatty acids reduce both plasma and
correlated with histological improvement and histological non- liver lipids, but there are no data to support their use
responders did not reduce ALT [131]. In the paediatric TONIC trial specifically for NASH (B1)
[98], vitamin E failed to reduce aminotransferases, steatosis and
inflammation but improved ballooning and doubled the rate of
NASH clearance vs. placebo. These results contrast with previous
trials, which were mostly negative in both adults and children.
Concerns about long-term safety of vitamin E exist, mainly an Iron depletion
increase in overall mortality [132], in haemorrhagic stroke
[133] and prostate cancer in males older than 50 [134]. Vitamin Hepatic iron accumulation is associated with IR, and iron deple-
E may be used in non-cirrhotic non-diabetic NASH patients but tion improves IR [138]. In NAFLD, high ferritin levels are common,
further studies are needed before firm recommendations can be in the presence of variable transferrin saturation, independent of
made. gene polymorphisms of familial hemochromatosis. In these
Ursodeoxycholic acid (UDCA) has been investigated in several patients, a phlebotomy programme to reduce iron stores to near
RCTs, at different doses and for up to 2 years, but only showed iron deficiency improved the NAS score, without worsening fibro-
some biochemical but no histological improvements [83,87,96]. sis [100], but more data are needed.
A synthetic farnesoid X receptor agonist, obeticholic acid,
improved IR in T2DM [135]. In the phase IIb FLINT trial, a 72-
Paediatric NAFLD
week treatment with obeticholic acid in non-cirrhotic NASH
patients, improved all NASH lesions while improving fibrosis
In children, diet and exercise training reduce steatosis, but do not
[99]. Main issues with safety and tolerability were increased
affect ballooning, inflammation and fibrosis [139]. Although sev-
low-density lipoprotein (LDL)-cholesterol and pruritus.
eral drug-based therapies, such as vitamin E and metformin, and
Preliminary data from small or uncontrolled studies suggested
dietary supplementation, including probiotics and docosahex-
that n-3 polyunsaturated fatty acids (PUFA) might reduce liver fat
aenoic acid, have shown beneficial effects on ballooning, steatosis
[136], but two trials testing PUFA on histological outcomes were
and inflammation, fibrotic lesions are refractory to treatment
negative [102,104]. Available data on pentoxifylline and orlistat
[140] and the long-term outcome of paediatric NASH remains
are limited or inconclusive [86,91,97]. Also, data on lipid-lowering
poor [141].
drugs are poor; recent trials with ezetimibe were negative
[101,103], whereas statins have not been adequately tested. Their
Recommendations
use in NAFLD is safe, with no increased risk of hepatotoxicity, and
may even significantly reduce aminotransferases [137].
Promising novel agents with anti-inflammatory, antifibrotic
or insulin sensitizing properties (dual PPARa/d agonists, dual Diet and physical activity improve steatosis and hepatic
inflammation in paediatric NAFLD, but no beneficial
chemokine receptor [CCR]2/CCR5 antagonists and fatty acid/bile
effects on fibrosis have ever been demonstrated. No
acid conjugates) and antifibrotic agents (anti-lysyl oxidase-like
safe drug treatment has proven effective on fibrosis in
[anti-LOXL2] monoclonal antibodies) are also being tested in paediatric NAFLD (B1)
late-phase RCTs in NASH.
Conflict of interest Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jhep.2015.11.
Giulio Marchesini declares he does not have anything to disclose 004.
regarding funding or conflict of interest with respect to this
manuscript.
Christopher P. Day declares he has been a consultant/advisor for References
Abbott Laboratories and Genfit and completed sponsored lectures
for Abbott Laboratories. [1] Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position
Jean-Franois Dufour declares he has been a consultant/advisor statement on NAFLD/NASH based on the EASL 2009 special conference. J
Hepatol 2010;53:372384.
for Intercept and Genfit.
[2] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al.
Ali Canbay declares he does not have anything to disclose regard- GRADE: an emerging consensus on rating quality of evidence and strength
ing funding or conflict of interest with respect to this manuscript. of recommendations. BMJ 2008;336:924926.